title: Environmental neurotoxin dieldrin induces apoptosis via caspase-3-dependent proteolytic activation of protein kinase C delta (PKCdelta): Implications for neurodegeneration in Parkinson's disease.
abstract: BACKGROUND
  In previous work, we investigated dieldrin cytotoxicity and signaling cell death mechanisms in dopaminergic PC12 cells. Dieldrin has been reported to be one of the environmental factors correlated with Parkinson's disease and may selectively destroy dopaminergic neurons.
  
  
  METHODS
  Here we further investigated dieldrin toxicity in a dopaminergic neuronal cell model of Parkinson's disease, namely N27 cells, using biochemical, immunochemical, and flow cytometric analyses.
  
  
  RESULTS
  In this study, dieldrin-treated N27 cells underwent a rapid and significant increase in reactive oxygen species followed by cytochrome c release into cytosol. The cytosolic cytochrome c activated caspase-dependent apoptotic pathway and the increased caspase-3 activity was observed following a 3 hr dieldrin exposure in a dose-dependent manner. Furthermore, dieldrin caused the caspase-dependent proteolytic cleavage of protein kinase C delta (PKCδ) into 41 kDa catalytic and 38 kDa regulatory subunits in N27 cells as well as in brain slices. PKCδ plays a critical role in executing the apoptotic process in dieldrin-treated dopaminergic neuronal cells because pretreatment with the PKCδ inhibitor rottlerin, or transfection and over-expression of catalytically inactive PKCδ(K)³⁷⁶(R), significantly attenuates dieldrin-induced DNA fragmentation and chromatin condensation.
  
  
  CONCLUSIONS
  Together, we conclude that caspase-3-dependent proteolytic activation of PKCδ is a critical event in dieldrin-induced apoptotic cell death in dopaminergic neuronal cells.
authors.affiliation: Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, USA. akanthas@iastate.edu
authors.forename: Anumantha G
authors.initials: AG
authors.lastname: Kanthasamy
authors.forename: Masashi
authors.initials: M
authors.lastname: Kitazawa
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Yang
authors.forename: Vellareddy
authors.initials: V
authors.lastname: Anantharam
authors.forename: Arthi
authors.initials: A
authors.lastname: Kanthasamy
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D055162:Biocatalysis / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism*; D061945:Caspase Inhibitors; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004026:Dieldrin / Q000633:toxicity*; D004785:Environmental Pollutants / Q000633:toxicity; D004789:Enzyme Activation / Q000187:drug effects; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism; D009410:Nerve Degeneration / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity; D010300:Parkinson Disease / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D051745:Protein Kinase C-delta / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D061945:Caspase Inhibitors; D004785:Environmental Pollutants; D050505:Mutant Proteins; D009498:Neurotoxins; D017382:Reactive Oxygen Species; D045304:Cytochromes c; D051745:Protein Kinase C-delta; D053148:Caspase 3; D004026:Dieldrin